Familial haemolytic uraemic syndrome and an MCP mutation

Lancet. 2003 Nov 8;362(9395):1542-7. doi: 10.1016/S0140-6736(03)14742-3.

Abstract

Background: Mutations in factor H (HF1) have been reported in a consistent number of diarrhoea-negative, non-Shiga toxin-associated cases of haemolytic uraemic syndrome (D-HUS). However, most patients with D-HUS have no HF1 mutations, despite decreased serum concentrations of C3. Our aim, therefore, was to assess whether genetic abnormalities in other complement regulatory proteins are involved.

Methods: We screened genes that encode the complement regulatory proteins-ie, factor H related 5, complement receptor 1, and membrane cofactor protein (MCP)-by PCR-single-strand conformation polymorphism (PCR-SSCP) and by direct sequencing, in 25 consecutive patients with D-HUS, an abnormal complement profile, and no HF1 mutation, from our International Registry of Recurrent and Familial HUS/TTP (HUS/thrombotic thrombocytopenic purpura).

Findings: We identified a heterozygous mutation in MCP, a surface-bound complement regulator, in two patients with a familial history of HUS. The mutation causes a change in three aminoacids at position 233-35 and insertion of a premature stop-codon, which results in loss of the transmembrane domain of the protein and severely reduced cell-surface expression of MCP.

Interpretation: Results of previous studies on HF1 indicate an association between HF1 deficiency and D-HUS. Our findings of an MCP mutation in two related patients suggest that impaired regulation of complement activation might be a factor in the pathogenesis of genetic forms of HUS. MCP could be a second putative candidate gene for D-HUS. The protein is highly expressed in the kidney and plays a major part in regulation of glomerular C3 activation. We propose, therefore, that reduced expression of MCP in response to complement-activating stimuli could prevent restriction of complement deposition on glomerular endothelial cells, leading to microvascular cell damage and tissue injury.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Antigens, CD / genetics*
  • Complement Factor H / genetics
  • Complement Inactivator Proteins / genetics*
  • Complement System Proteins / genetics*
  • Complement System Proteins / physiology
  • Female
  • Hemolytic-Uremic Syndrome / epidemiology
  • Hemolytic-Uremic Syndrome / genetics*
  • Hemolytic-Uremic Syndrome / physiopathology
  • Humans
  • Kidney Glomerulus / physiopathology
  • Male
  • Membrane Cofactor Protein
  • Membrane Glycoproteins / genetics*
  • Mutation*
  • Pedigree
  • Polymerase Chain Reaction / methods
  • Polymorphism, Single-Stranded Conformational
  • Receptors, Complement / genetics

Substances

  • Antigens, CD
  • CD46 protein, human
  • Complement Inactivator Proteins
  • Membrane Cofactor Protein
  • Membrane Glycoproteins
  • Receptors, Complement
  • complement factor H, human
  • Complement Factor H
  • Complement System Proteins